Hepatic accumlation [sic] of myofibroblastic hepatic stellate cells (MF-HSC) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSC to accumulate in damaged livers: 1) transition of resident, quiescent HSC (Q-HSC) to MF-HSC, and 2) further expansion of MF-HSC numbers via increased proliferation and/or reduced apoptosis. Our group has identified two novel mediators of MF-HSC accumulation: Rac1 and Hedgehog (Hh). Recently, we have accumulated evidence that the first event (transition to MF-HSC) involves epithelial-to-mesenchymal (EMT) and shown that Hh signaling promotes EMT in another type of resident liver cell (ie, ductular-type progenitors cells (DPC)). Our earlier publications demonstrate that both Rac1 and Hh promote proliferation of MF-HSC while inhibiting their apoptosis. The general goal of this project is to determine if Rac1 and Hh interact to regulate the accumulation of MF-HSC after liver damage. This project evaluates the HYPOTHESIS that Rac1 promotes the activation of the Hh pathway, thereby stimulating signals that promote epithelial-to-mesenchymal transition in Q-HSC, and that enhance the viability of MF-HSC. Two Specific Aims will be addressed: Aim 1 will determine if Rac1 inhibits Hedgehog-interacting protein (Hip) to promote Hh signaling-mediatd [sic] EMT in HSC; Aim 2 will determine the impact of altering Rac1 activity on Hh pathway activation and liver fibrotic response to toxin-induced liver injury. In both in vitro and in vivo model systems, Rac1 signaling will be manipulated via genetic approaches (eg, adenoviral vector-mediated delivery of constitutively active or dominant negative Rac1) and pharmacologic agents (eg, pathway agonists and antagonists). We hope to delineate a signaling cascade by which the cytoskeletal protein Rac1 interacts with a morphogenic signaling pathway (Hh) to reprogram gene expression in Q-HSC, promoting myofibroblastic transition, and enhancing MF-HSC proliferation and survival.